13,17-dialkyl-19-norpregn-4-ene,3,20-diones

ABSTRACT

THE COMPOUNDS OF THE CLASS OF 13,17-DIALKYL-18,19-DINORPREGN-4-EN-3,20-DIONES AND 13,17,21,21,21-PENTAALKYL18,19-DI-NORPREGN-4-EN-3,20-DIONES ARE PREPARED AND FOUND TO BE HORMONALLY USEFUL.

United States Patent @oe 3,594,407 13,17-DIALKYL-19-NORPREGN-4-ENE, 3,20-DIONES Daniel M. Teller, King of Prussia, George H. Douglas, Chester, and Herchel Smith, Delaware, P2,, assignors to vAmerican Home Products Corporation, New York,

No Drawing. Continuation-impart of application Ser. No. 614,410, Feb. 7, 1967. This application Apr. 3, 1969, Ser. No. 813,284

Int. Cl. C07c 169/08 U.S. Cl. 260-3975 8 Claims ABSTRACT OF THE DISCLOSURE The compounds of the class of 13,17-dialky1-18,19-dinrpregn-4-en-3,20-diones and 13,17,2l,21,21-pentaalkyl- 18,19-dinorpregn-4-en-3,20-diones are prepared and found to be hormonally useful.

More particularly, this invention relates to compounds of the Formulae I and II:

and

wherein R represents an alkyl group of from 2 to 8 carbon atoms; R represents an alkyl group of less than carbon atoms; R is selected from the group consisting of R and 3,594,407 Patented July 20, 1971 hydrogen; R represents hydrogen; and R represents hydroxy, or together R and R represents oxo (=0).

The final products of this invention are physiologically active substances which are useful as androgen antagonists. It has also been found that the 13,17-dialkyl-18,19- dinorpregn-4-en-3,20 diones, shown below as Formula IXa have both oral and strong parenteral progestational and anti-estrogenic activity as determined under standard pharmacological procedures at different dosage levels from 10 to 100071, in animals.

The compounds may be formulated for such administration, the concentration and/or dosage being based on the activity of the particular compound and the requirements of the patient.

The compounds of this invention may be prepared according to the process of this invention which may be represented by the following reaction scheme Werein R, R R R R R and R are as hereinbefore defined:

IX IXa According to a feature of this invention, the 17B-acetyl- 13-alkyl 3 rnethoxygona-1,3,5(10)-triene compound (III) is converted by a known process to the corresponding 3-methoxy-A -20-enol-acetate (IV). Such process consists in reacting the 20-ketone steroids (III) with an acylating agent such as acetic anhydride, in the presence of a strongly acidic catalyst, such as p-toluenesulfonic acid, sulfuric acid or perchloric acid.

The compounds of Formula III are known compounds which may be prepared by any conventional method, such as described in copending application Ser. No. 534,353 of G. A. Huges et al. filed Mar. 15, 1966.

The 3-methoxy-A -ZO-enol acetate compounds (IV) are then alkylated with an alkyl halide, such as methyl iodide, ethyl chloride, propyl chloride, butyl bromide, and the like, in liquid ammonia to yield the 3-methoxy-A -17-alkyl-20-keto steroids of Formula Va and the novel 3-methoxy-A -17,21,2l,-trialkylor 17,21,21,21-tetra-alkyl-20-keto steroids of Formula V.

The 3 methoxy-A -17-alkyl-2l-polyalkylated-ZO- keto steroids of Formula V are then reduced with a reducing agent, such as sodium borohydride, to yield the corresponding 3 methoxy-A -17-alkyl-2l-polyalkylated-ZO-hydroxy steroids of Formula VI, which are further novel intermediates of the invention.

Subsequent reduction of the 3-methoxy-A -17- alkyl-21-polyalkylated-20-hydroxy steroid (VI) in liquid ammonia with lithium and a lower alkanol yields the corresponding 3 methoxy-A -17-alkyl-2l-polyalkylated- 20-hydroxy steroid (VII) which when treated with concentrated hydrochloric acid yields the novel 3-keto-A -17- alkyl-2l-polyalkylated-ZO-hydroxy steroids (VIII).

Treatment of the 3-keto-A -17-alkyl-2l-polyalkylated- 20-hydroxy steroids (VIII) with an oxidizing agent such as Jones reagent (8 N CrO yield the A -17-alkyl-21- polyalkylated-3,20-diketo steroids of Formula IX, which are novel final products of this invention.

Treatment of the 3-methoxy-A -l7-alkyl-20-keto steroids of Formula Va, similar to the process described for 2l-polyalkylated compounds of Formula V, yields upon reduction with sodium borohydride the 3-methoxy- A -17-alkyl-20-hydroxy steroids of Formula VIa. Further reduction of VIa in liquid ammonia with lithium and a lower alkanol yields the corresponding 3-methoxy- A -17-a1kyl-20-hydroxy steroids (VIIa) which, when treated with concentrated HCl which yields the 3-keto- A -20-hydroxy steroid of Formula VIIIa.

To obtain the 4,20-diketo steroids of Formula IXu, which are additional final products of this invention, the 3-keto-A -20-hydroxy steroids (VIIIa) are treated with an oxidizing agent, such as Jones reagent.

The .following examples illustrate the invention (all temperatures being in centigrade):

EXAMPLE 1 13-ethyl-3-methoxy-18, 19-dinorpregna-1,3,5 10) 17 (20)- tetraen-ZO-ol, acetate A solution of 1.00 gm. of 17fi-acetyl-l3-ethyl-3-methoxygona-1,3,5(10)-triene and 0.53 gm. of p-toluenesulfonic acid in ml. of acetic anhydride is slowly distilled through a short Vigreux column at atmospheric pressure over a 4 hour period leaving approximately 30 ml. of brown residue. The residue is cooled in an ice bath, 100 ml. of water is added and the mixture is stirred for 15 minutes. The mixture is then extracted with ether and the ether extracts washed with 10% aqueous sodium hydroxide, saturated aqueous sodium bicarbonate, water, dried over anhydrous magnesium sulfate and the solvent is evaporated in vacuo yields a brown gum. Column chromatography of the gum on 60 gm. of Florisil using 100% hexane as eluant gives, after recrystallization from methanol, 350 mg. of colorless solid which, on recrystallization from methanol, yields 13-ethyl-3-methoxy-18,19-dinorpregna-1,3,5(10),17(20)-tetraen-20-ol, acetate having a melting point of 8992;

A122; 5.71, 5.88, (weak); A519,? 284 m (e=1,660)

Analysis.Calcd. for C H O (percent): C, 78.22; H, 8.75. Found (percent): C, 78.22; H, 8.63.

EXAMPLE 2 13 3-propyl-3-methoxy-18,19-dinorpregna- 1,3,5 l0),17 (20)-tetraen-20-ol, acetate Following the procedure of Example 1 but substituting 17fi-acetyl-13fi-propyl 3 methoxygona-1,3,5(10)-triene for 17fl-acetyl-13-ethyl 3 methoxygona-1,3,5 (10)-triene there is obtained 13,8-propyl-3-methoxy-18,19-dinorpregna-1,3,5( 10),17(20)-tetraen-20-ol, acetate.

EXAMPLE 3 13 fl-butyl-3-methoxxy-1 8,19-dinorpregna-1,3,5 10 17 (20 -tetraen-20-ol, acetate Following the procedure of Example 1 but substituting 17,8-acetyl-13,8-butyl-3-methoxygona-1,3,5(10)-triene for 17 j8-acetyl- 1 3-ethyl-3 -methoxygona-1 ,3,5 10 -triene there for 17/3-acetyll 3-ethyl 3 methoxygona- 1 ,3,5( 10 -triene is obtained 13 ,8-butyl-3-methoxy-18, 19-dinorpregna-1,3, 5( 10),17(20)-tetraen-20-ol, acetate.

EXAMPLE 4 13fi-isobutyl-3-methoxy-18,19-dinorpregna-l,3,5(10), 17(20)-tetraen-20-ol, acetate Following the procedure of Example 1 but substituting for acetyl-13/3-isobutyl-3-methoxygona-l,3,5(l0)-triene there is obtained 13,8-isobutyl-3-methoxy-l8,19-dinorpregna-l,3,5(10),l7(20)-tetraen-2-ol, acetate.

EXAMPLE 5 13,8-ethy1 3 methoxy-17,21,21-trimethyl 18,19 dinorpregna-1,3,5()-trien-20-one and 13B-ethyl-3-methoxy- 17-methyl-18,19-dinorpregna-l,3,5(10)-trien-20-one To 4.0 gm. quantity of potassium dissolved in 2,000 ml. of liquid ammonia is added a few crystals of ferric nitrate to discharge the blue color. A solution of 9.90 gm. of l3B-ethyl-3-methoxy 18,19 dinorpregna-1,3,5 (10 l7(20)-tetraen-20-ol, acetate in 600 ml. of distilled ether is then added over a minute period and the mixture was stirred for 8 hours. 20.0 ml. of methyl iodide is added and after stirring 30 minutes another 10.0 ml. of methyl iodide is added. The mixture is stirred an additional 30 minutes and a further 10.0 ml. of methyl iodide is added. The mixture is then stirred 30 minutes and m1. of 95% ethanol is added.

The ammonia is evaporated and water and benzene is added. The organic layer is washed with 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water, dried over anhydrous sodium sulfate and the solvent is evaporated in vacuo. Crystallization of the gummy residue from isopropanol yields 4.60 g. of colorless solid.

The solid and mother liquor from the crystallization was combined and columned on Grade I Woelm neutral alumina. Elution with hexane and increasing proportions of benzene and recrystallization from isopropanol yields 0.75 gm. of 13B-ethyl-3-methoxy-l7,2l,21-trimethyl-l8, 19-dinorpregna-.1,3,5(10)-trien-20-one having a melting point of ll8120;

A233; 5.9 A523? 283 u Analysis.-Ca1cd. for C H O (percent): C, 81.47; H, 9.85. Found (percent): C, 81.37; H, 9.57.

Later fractions from the column chromatography were recolumned on the same adsorbent. Elution with hexane containing increasing proportions of benzene gave 1.57 gm. of 13,3-ethyl-3-methoxy-17-methyl-18,19-dinorpregna- 1,3,5(10)-trien-20-one having a melting point of 144- 148;

EtOH

Analysis.Calcd. for C H O (percent): C, 81.13; H, 9.47. Found (percent): C, 81.46; H, 9.82.

EXAMPLE 6 13,6-ethyl-3-methoxy-17,21,21,21-tetramethyl-l8,l9- dinorpregna-1,3 ,5 10) -trien-20-one Following the procedure of Example 5 there is also obtained in admixture, 13fi-ethyl-3-methoxy-17,21,2l,21- tetramethyl-l8,19-dinorpregna-1,3,5 10) -trien-20-one.

EXAMPLE 7 13B ethyl methoxy 17,21,21 triethyl 18,19 dinorpregna l,3,5(10 trien 20 one and 133- ethyl 3- methoxy 17 ethyl 18,19 dinorpregna l,3,5(10)- trien-ZO-one Following the procedure of Example 5, but substituting ethyl chloride .for methyl iodide there is obtained 13,6- ethyl 3 methoxy 17,21,21 triethyl 18,19 dinorpregna l,3,5(10) trien 20 one and 13,8 ethyl 3- methoxy 17 ethyl 18,19 dinorpregna l,3,5(10)- trien-20-one.

' EXAMPLE 8 13/8 ethyl 3 methoxy 17,21,21 tributyl 18,19 dinorprenga l,3,5(10) trien 20 one and 135 ethyl- 3 methoxy l7 butyl 18,19 dinorpregna 1,3,5

(10) -trien-20-one Following the procedure of Example 5, but substituting butyl bromide for methyl iodide there is obtained 13B- ethyl 3 methoxy 17,21,21 tributyl 18,19 dinorpregna l,3,5(10) trien 20 one and 135 ethyl 3 methoxy 17 butyl 18,19 dinorpregna 1,3,5 (10) trien- 20-one.

6 EXAMPLE 9 13B propyl 3 methoxy 17,21,21 trimethyl 18,19- dinorpregna l,3,5(10) trien 20 one and 13B- propyl 3 methoxy 17 methyl 18,19 dinorpregna- 1,3,5 10)-trien-20-one Following the procedure of Example 5, but substituting 13 3 propyl 3 methoxy 18,19 dinorpregna 1,3,5 (l0),17(20)-tetraen-20-ol, acetate for 13fl-ethyl-3-methoxy 18,19 dinorpregna l,3,5(10),17(20) tetraen- 20-01, acetate there is obtained l3fl-propyl-3-methoxy-l7, 21,21 trimethyl -l 8,19 dinorpregna l,3,5(10) trien- 20 one and 13d propyl 3 methoxy 17 methyl- 18,19-dinorpregna-1,3,5(10)-trien-20-one.

EXAMPLE 10 13,8 butyl 3 methoxy 17,21,21 trimethyl 18,19- dinorpregna l,3,5(10) trien 20 one and 13B butyl 3 methoxy 17 methyl 18,19 dinorpregna 1,3, 5(10)-trien-20-one Following the procedure of Example 5, but substituting 13B butyl 3 methoxy 18,19 dinorpregna 1,3,5 (10),l7(20)-tetraen-20-ol, acetate for 13,8-ethyl-3-methoxy 18,19 dinorpregna- -1,3,5(10),17(20) tetraen- 20-01, acetate there is obtained 13/3-butyl-3-methoxy-l7, 21,21 trimethyl 18,19 dinorpregna l,3,5(10) trien- 20 one and 13B butyl 3 methoxy 17 methyl 18, 19-dinorpregna-l,3,5 (10)-trien-20-one.

EXAMPLE 11 13 isobutyl 3 methoxy 17,21,21 trimethyl 18,19- dinorpregna l,3,5(10) trien 20 one and 135 isobutyl 3 methoxy 17 methyl 18,19 -dinorpregna- 1,3,5 10) -trien-20-one Following the procedure of Example 5 but substituting 13p isobutyl 3 methoxy 18,19 dinorpregna 1,3,5 (l0),17(20)-tetraen-20-ol, acetate for l3B-ethyl-3-methoxy 18,19 dinorpregna 1,3,5(l0),17(20) tetraen-20- ol, acetate there is obtained 13fi-isobutyl-3-methoxy-17,21, 21 trimethyl 18,19 dinorpregna l,3,5(10) trien 20- one and 135 isobutyl 3 methoxy 17 methyl 18,19- dinorpregna-1,3,5 l0) -trien-20one.

EXAMPLE l2 13B-ethyl-3-methoxy-17-methyl-18,l9-dinorpregna- 1,3,5 10) -trien-20-o1 A suspension of 0.80 gm. of 13,8-ethyl-3-methoxy-l7- methyl 18,19 dinorpregna 1,3,5 (10) trien 20 one and 1.60 gm. of sodium borohydride in ml. of absolute ethanol is stirred at room temperature for 17 hours. Excess glacial acetic acid is added, ether is added, the solution is washed with Water, saturated aqueous sodium bicarbonate, water, dried over anhydrous sodium sulfate and the solvent is evaporated in vacuo to yield 0.89 gm. of 138 ethyl 3 methoxy 17 methyl 18,19 dinorpregna-1,3,5(10)-trien-20-ol.

EXAMPLE 13 13fl-ethyl-3-methoxy-17,21,21-trimethyl-l8,19- dinorpregna-1,3,5 10) -trien-20-ol tively, the products of the following Examples 14 through 24:

Starting material Ex. Ex.

No. No. Product Product 14- G 13B-cthyl-3-1neth0xy-17, 21, 13/3-ethyl-3-methoxy-17, 21,

21, 21-tctramethyl-18, 19- 21, 21-tetrarnctlryl-18, 19- dinorpregna-l, 3, 5(10) dinorpregnad, 3, 5 (10) trien-20-one. tncn-20-ol.

15. 7 l3fi-ethyl-3-rnetl1oxy-17, 21, 133-ethyl-3-methoxy-l7, 21,

21-trientl1yl-18, 19- 21, -tricthyl-18, 19 dinorpregna-1, 3, 5 (10)- dinorpregna-l, 3, 5(10) trien-20-one. tn'en-20-ol.

16. 7 13/9-ethyl-3-n1ethoxy-17- 13B-ethyl-3-methoxy-17- ethyl-18, ltl-dinorpregnaethyl-18, 19-dinorpregna- 1, 3, 5(10) mien-20 0110. 1, 3, 5(10) -trien-2O-0l.

17. 8 1313 ethyl-3-metl1oxy-17, 13fl-ethyl-3-methoxy-17,

21, 21-tributyl-18, 19- 21, 21-tributyl-18, 19 dinorpregna-l, 3, 5 (10) dinorpregna-l, 3, 5(10) mien-200m. trien-200l.

18- 8 13fiethyl-3-methoxy-17- 1313-ethyl-3-methoxy-17- butyl-IS, 19 dinorpregnabutyl-18, lg-dinorpregna- 1, 3, 5( 10) -tn'en-20-one. 1, 3, 5(10) -trien-20-ol.

19. 9 13fl-p10pyl-3-methoxy-17, 13B-propyl-3-methoxy-17,

21, 2l-tn'1nethyl-18, 19- 21, 2l-tn'methyl-18, 19- dinorpregna-l, 3, 5(10) dinorpregna-l, 3, 5 (10) tlien-ZO-one, trien-200l.

20. 9 l3fl-propy1-3-methoxy-17- 135-1)ropyl-3-methoxy-17- methyl-18, 19dinorpre namethyl-18, 19-dinorpregna- 1, 3, 5(10)-trien-20-0ne. 1, 3, 5(10)-trien-20ol.

21 l 1313-butyl-3-meth0xy-17, 13fi-butyl'3-methoxy-17, 21,

21, 21-trimethyl-18, 19- -t 1 ethyl-18, 19- dinorpregna-l, 3, dinorprogna-l, 3, 5(10) trien--one. trien-20-ol.

22 10 13 3-butyl3-methoxy-17- 13fi-butyl-3-metl1oxy-17- methyl-18, lfil-dinorpregnamethyl-18, 19-(linorpregna- 1, 3, 5(10) -trien-20-0ne. 1, 3, 5(10) -t1*ien-20-ol.

23. 11 13B-etl1yl-3-mcthoxy-17, 13BiSobutyl-3-metl1oxy-17,

21, 21-trin1ethyl-18, 10- 21, 21-trirnethyl-18, 19- dinorpregna-l, 3, 5(10) dinorpregna-l, 3, 5(10) trien-20-oue. trien-20-ol.

methyl-18, lQ-dinolpregnamethyl-18,19-din0rpregna- 1, 3, 5 (10) -trien-20-one. 1, 3, 5(10) -trien-20-ol.

EXAMPLE 13fi-ethyl-3-methoxy-17-methyl-18,19-dinorpregna- 2,5(10)-dien-20-o1 0.89 gm. of 13fi-ethyl-3-methoxy-17-methy1-18,19-dinorpregna-l, 3,5 (10)-trien-20-ol in 50 ml. of distilled tetrahydrofuran is added to 100 ml. of distilled liquid ammonia over a 1 minute period. Immediately 0.40 g. of lithium is added in small pieces as rapidly as possible. The mixture is stirred for 2 hours and then 20 ml. of absolute ethanol is added over 20 minutes. Warm water is added and the solution is extracted with ether-benzene. The organic layer is washed with saturated aqueous sodium bicarbonate, water, dried over anhydrous sodium sulfate and the solvent evaporated in vacuo to yield 0.87 gm. of 13-ethyl-13-methoxy-l7-methyl-18,19-dinorpregna- 2,5 (10)-dien-20-ol as a colorless gum which crystallized on triturating with methanol. IR shows enol ether peaks at 5.89 and 6.00 1 and no aromatic adsorption.

Treatment of the products of Examples 13 through 24 according to the procedure of Examples 25 gives, respectively, the products of the following Examples 26 through 37:

19-dinorpregna-2,5 (10) -dien-20-ol.

8 EXAMPLE 3s 13 fi-ethyl-20-hydroxy-17-methyl-l8,19-dinorpregn- 4-en-3-one A suspension of 0.77 gm. of 13B-ethyl-3-methoxy-l7- methyl-l8,l9-din0rpregna-2,5(10)-dien-20-ol in 21.5 ml. of methanol, 1.46 ml. of concentrated hydrochloric acid and 0.92 ml. of water is stirred at room temperature for 1 hour. The mixture is then filtered and the filtrate is diluted with benzene, washed with saturated aqueous sodium bicarbonate, water, dried over anhydrous sodium sulfate and the solvent evaporated in vacuo to yield 0.77 gm. of 13b ethyl-ZO-hydroxy-17-methyl-18,19-dinorpregn-4-en- 3-one.

Treatment of the products of Examples 26 through 37 according to the procedure of Example 38 yields, respectively, the products of the following Examples 39 through dinorpregnA-en-Bnne.

EXAMPLE 5 1 13,8-ethyl-17-methyl-18,19-dinorpregn-4-en-3 ,20-dione To a solution of 0.30 gm. of 13-ethyl-20-hydroxy-17- methyl-18,19-dinorpregn-4-en-3-one in 32.0 ml. of acetone is added 1.6 ml. of 8 N CrO (Jones reagent) at 0 all at once. Stirring at 0 is continued for 15 minutes, excess isopropyl alcohol is added, benzene is adedd and then the suspension is filtered. The filtrate is washed with saturated aqueous sodium bicarbonate, water, dried over anhydrous sodium sulfate and the solvent is removed by evaporation in vacuo to yield 0.27 gm. of a yellow solid. Recrystallization of the solid from ethyl acetate-hexane yields 0.14 gm. of '13/3-ethyl-17-methyl-18,19-dinorpregn-4-en-3 ,ZO-dione having a melting point of -163 5.89, 5.99, 6.18 N123? 242 m (e=15,700)

Analysis.-Calcd. for C H O (percent): C, 80.44; H, 9.83. Found (percent): C, 80.48; H, 10.17.

Oxidation of the products of Examples 39 through 50 according to the procedure of Example 51 yields, respec- 9 tively, the products of the following Examples 52 through 63:

It is understood that either dl-steroids or the specific dor l-isomers may be employed as starting materials with like results.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound selected from the group consisting of those of the formulae and wherein R is an alkyl group having from 2 to 8 carbon atoms; R is an alkyl group of less than carbon atoms; R is selected from the group consisting of R and hydrogen; R is hydrogen; R is hydroxy; and together R and R is oxo (:0).

10 2. A compound according to claim 1 having the structural formula wherein R and R are as hereinbefore defined.

3. A compound according to claim 2 that is 13fi-ethy1- 17-methyl-18,l9-dinorpregn-4-cn-3,20-dione.

4. A compound according to claim 1 that is 13fl,17,2l, 21-tetraalkyl-l8,l9-dinorpregna-4-en-3,20-dione.

5. A compound according to claim 4 that is IBB-ethyl- 17,21,21-trimcthyl-18,19-dinorpregn-4-en-3,20-dione.

6. A compound according to claim 1 having the structural formula wherein R and R are as hereinbefore defined.

7. A compound according to claim 6 which comprises 13B-ethyl-20-hydroxy-17-methy1-18,19-dinorpregn 4 en- 3-one.

8. A process for preparing steroids having the D-ring structure wherein R is an alkyl group having 2 to 8 carbon atoms; R is an alkyl group of less than 5 carbon atoms; and R is selected from the group consisting of hydrogen and alkyl of less than 5 carbon atoms which comprises reacting a steroid having the D-ring structure with at least two moles of an alkyl halide per mole of steroid.

References Cited Journal of the Chemical Soc. (1965) by Jones et al., pp. 2936 and 2942 relied on.

Chemistry and Industry (1963) by Weiss et al., pp. 118-119 relied on.

ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R. 260-397.4, 397.5 

